Janus porphyrin-stabilized phase-transition theranostics for multimodal imaging-guided synergistic cancer therapy

Acoustic and optical droplet vaporization (ADV/ODV) enables localized energy conversion through nanoscale phase transitions, offering a mechanism to couple imaging enhancement with therapeutic activation. However, achieving controlled vaporization while integrating multimodal imaging and therapy remains challenging. Here, we developed low-boiling-point fluorocarbons (FO1-FO4) as phase-transition liquids and Janus porphyrin amphiphiles (TP1 and TP2) as energy mediators, which co-assemble into core-shell nanodroplets (TFNP) that unify vaporization dynamics with multimodal theranostics. TFNP responds to optical or acoustic excitation by converting droplets into microbubbles, amplifying fluorescence, photoacoustic, and ultrasound signals, while simultaneously activating photodynamic and sonodynamic therapy. Structure-property optimization identified TP2 as an effective interfacial energy mediator, fluorophore, sonosensitizer, and photosensitizer, and FO1 as a newly developed phase-transition liquid with a single ¹⁹F resonance, enabling sensitive ¹⁹F magnetic resonance imaging (¹⁹F MRI) and controllable vaporization. Compared with the commonly used perfluorohexane, FO1 provides TFNP with unparalleled photoacoustic, ultrasound, and ¹⁹F MRI performance. Upon ADV/ODV triggering, TFNP synchronizes multimodal imaging enhancement with reactive oxygen species generation and anti-vascular effects, enabling spatially confined and temporally guided therapy. In vivo ¹⁹F MRI permitted quantitative tracking of FO1 retention and revealed a theranostic window of less than 10 hours for ADV/ODV nanodroplets. These findings demonstrate that rational molecular and interfacial engineering can significantly improve phase-transition theranostic performance while highlighting the importance of imaging-guided temporal optimization.